Developing gene therapies for specific neurological diseases, elucidating the etiology of these diseases, and genetic analyses of neuronal circuits, behaviors, and learning will all benefit from targeted gene transfer that can deliver different genes into presynaptic neurons and a selected subset of their postsynaptic neurons, based on both projection area and synapse type. Diseases that exhibit deficits in specific circuits include the major neurodegenerative diseases, and other major neurological disorders. Moreover, synaptic plasticity and neural network theories hypothesize that specific behaviors are encoded in specific circuits. Thus, targeted gene transfer across specific synapses will have broad applications to understanding and treating neurological diseases, and to basic neuroscience. To target gene transfer to specific neuron types, we modified a protein on the surface of Herpes Simplex Virus (HSV-1) vector particles; we replaced a panspecific cell binding domain with a neuron type-specific binding domain. In the initial study, we added specific neurotrophic factors to the surface of HSV-1 particles, targeting gene transfer to neurons that contain the cognate receptors. Next, we developed a general method to target gene transfer to specific neuron types, antibody-mediated targeting. We added the Staphylococcus A protein antibody binding domain to a vector particle protein. Complexes of these vector particles and specific antibodies supported targeted gene transfer. We developed targeted gene transfer to deliver different genes into presynaptic neurons and a selected subset of their postsynaptic neurons, based on both projection area and synapse type. The initial study targeted gene transfer across glutamatergic synapses. The first gene transfer, into the presynaptic neurons, uses standard procedures. The vector expresses an artificial peptide neurotransmitter that contains a dense core vesicle sorting domain, a neurotransmitter receptor binding domain (for NMDA NR1 subunits), and the His tag. Upon release, this peptide neurotransmitter binds to the cognate receptors on the postsynaptic neurons. Antibody-mediated targeting to these postsynaptic neurons uses a His tag antibody, as the peptide neurotransmitter contains the His tag. This targeting supported an ~10-fold increase in specificity. The long-term goal of this project is to develop targeted gene transfer across specific synapse types, for elucidating disease etiologies, developing gene therapies, and basic neuroscience. The proposed experiments will optimize targeted gene transfer across synapses, develop targeting across specific synapse types critical in neurology and neuroscience, and apply these advances to a problem in the etiology of Alzheimer's disease, thereby developing a novel gene therapy. Of note, these targeting strategies and reagents can be used in any gene transfer system.